Anomaly of Triglyceride Metabolism in Liver Lead to NAFLD

ISSN 1007-7626 CN 11-3870 / Q http / /cjbmb. bjmu. edu. cn Chinese Journal of Biochemistry and Molecular Biology 2016 2 32 2 123 ~ 132 DOI 10. 13865 /j. cnki. cjbmb. 2016. 02. 02 * 100191 NAFLD β Q542 Anomaly of Triglyceride Metabolism in Liver Lead to NAFLD WEI Su-Ning SU Xue-Ying XU Guo-Heng * Department of Physiology and Pathologic Physiology Peking University Basic Medical School Beijing 100191 China Abstract Non-alcoholic fatty liver disease NAFLD is an independent or concomitant metabolic disease associated to obesity lipodystrophy and diabetes. NAFLD is characterized by accumulation of triglyceride in hepatocytes. Factors influencing metabolisms of triglyceride in liver can be involved for inducing NAFLD. There are two sources of liver fatty acid one is from fatty acid uptake from circulation and the other is from fatty acid de novo synthesis. Under physiological conditions fatty acid uptake plays a leading role in triglyceride production. But in NAFLD fatty acid de novo synthesis is more important for triglyceride accumulation. Fatty acid can enter mitochondria for β-oxidation and generate ketone bodies which can be uptaken by myocardium brain and skeletal muscle. Triglyceride produced by fatty acid esterification will be packaged into VLDL and secrete to plasma. Factors affect these four pathways will disturb the homeostasis of triglyceride metabolism causing accumulation anomaly. The triglyceride accumulation in liver can damage insulin sensibility stimulate gluconeogenesis and induce hyperglycemia. Triglyceride accumulated in hepatocytes will accelerate VLDL packaging and secretion then lead to hyperglyceridemia. This review focused on pathways of triglyceride metabolism in the context of available drug targets for NAFLD treatments. Key words non-alcoholic fatty liver disease NAFLD triglyceride fatty acid de novo synthesis fatty acid β oxidation fatty acid uptake 25% 1 2015-05-13 2015-09-25 No. 2 91439119 A E-mail xug@ bjmu. edu. cn * Tel 13521052157 E-mail xug@ bjmu. edu. cn Received May 13 2015 Accepted September 25 2015 Supported by National Natural Science Foundation of China No. 91439119 * Corresponding author Tel 13521052157

124 32 1 very low density lipoprotein VLDL fatty acid transport protein FATP 4 fatty acid binding protein FABP FAT /CD36 β VLDL 3 Fig. 1 Fig. 1 Triglyceride metabolism in liver There are four major triglyceride metabolism pathways in liver. FFA uptake is mediated by FATP FABP and CD36. ACC1 FAS ELOVL6. SCD1 is key rate-limiting enzymes in fatty acid synthesis. Fatty acid synthesis can be triggered by glucolysis whose rate-limiting enzymes are GK and LPK. The rate of fatty acid beta oxidation is controlled by CPT1A whose activity can be inhibited by malonyl-coa. Triglyceride can be transported by MTTP to endoplasmic reticulum to form VLDL with apob

2 125 1. 1 FATP FATP Fatp5 - / - 1. 2 FABP A very long-chain FABP acyl-coa synthetase ACSVL 3 FABP Liver FABP L-FAPB 8 L-FABP A FATP 9 ACSVL Table 1 FATP2 FATP5 4 FATP2 FATP5 β HuH7 HepG2 FATP2 8 L-Fapb - / - FATP2 14 C- L-FABP FATP2 ACSVL L- A Fapb - / - L-Fapb - / - 5 Fatp2 10 L-FABP ACSVL L- 40% FATP2 FABP A L-FABP 6 FATP5 L-Fapb - / - Fatp5 - / - 14 C- β L-FABP 50% 7 Fatp5 - / - β 11 FAS L-Fapb - / - β Fatp5 - / - L-FABP CPT1 Fatp5 - / - L-FABP A Table 1 FATP family Human gene Protein Alias Tissue distribution SLC27A1 FATP1 ACSVL5 Bat wat heart skeletal muscle skin brain kidney endothelial cells SLC27A2 FATP2 ACSVL1 Liver kidney cortex placenta SLC27A3 FATP3 ACSVL3 Skin adrenal gland testis ovary brain lung endothelial cells SLC27A4 FATP4 ACSVL4 Small intestine skin placenta brain skeletal muscle WAT endothelial cells SLC27A5 FATP5 ACSVL6 Liver SLC27A6 FATP6 ACSVL2 Heart skin 1. 3 CD36 CD36 CD36 14 CD36 CD36 CD36 2 12 ob /ob CD36 2. 1 CD36 13 CD36 γ peroxisome

126 32 sterol regulatory element-binding γ2 25 KKA y PPAR- proteins SREBP γ1 26 PPARγ carbohydrate responsive element-binding protein PPARα - / - ChREBP PPAR-γ1 27 PPARγ TZD PPARγ PPARγ PPARγ 28 AZIP PPARγ perilipin KKA y SREBP TZD 3 26 SREBP1-a SREBP-1c SREBP2 15 2. 1. 2 SREBP SREBP 3 SREBP1-a SREBP SREBP cleavage-activating protein SCAP SREBP2 29 SREBP1-a SREBP SREBP S1P S2P 15 SREBP SREBP SREBP 29 SREBP-1c SREBP-1c 29 SREBP2 glucokinase GK 30 Shimano A 1 acetyl coenzyme A carboxylase 1 ACC1 fatty acid synthase FAS 15 SREBP1-a ACC1 SREBP1-a 5 FAS HMG-CoA 26 SREBP-1c HMG-CoA reductase SREBP2 15 ChREBP 4 SREBP2 16 28 4 5-6- 2 17 ChREBP liver 33 SREBP1-a pyruvate kinase LPK 17 18 ACC1 FAS A SREBP1 SREBP2 stearoyl-coa desaturase-1 SCD1 SREBP - / - 2. 1. 1 PPARγ PPARγ 50% 85% 11 d γ 1 γ 2 PPAR-γ2 SREBP2 SREBP1 - / - PPAR-γ1 3 34 AGPAT2 - / - SCAP AZIP ob /ob KKA y SCAP SREBP SREBP PPARγ 19-22 S1P S2P 15 PPARγ ob /ob AZIP SCAP SREBP 23 24 35 14 C PPARγ ob /ob proliferators activated receptors γ PPARγ db /db AZIP PPAR- SREBP-1c mrna 31 SREBP1-a SREBP-1c SREBP2 3 32 3 SREBP SREBP-1c 14 C

2 127 14 C SCAPLKO A ACC2 280 kd SREBP A 36 2. 1. 3 ChREBP ChREBP ACC1 16 37 ACC2 β Northern ChREBP ACC1 ACC2 12. 5 d ChREBP ChREBP > 40-42 > > = ChREBP ChREBP ACC1 - / - ACC1 + /- 38 ChREBP ACC1 mrna 1 /2 ChREBP ACC1 + /- ob /ob ChREBP mrna β 38 ChREBP 39 43 ACC1 ob /ob ChREBP ACC2 ob /ob ACC1 ACC2 38 39 A 44 ChREBP - / - fructokinase FK pyruvate kinase LPK mrna 2- furancarboxylic acid 59% 27% 16 ACC1 FAS ACC1 16 A 30% ChREBP - / - 50% 1 β ACC1 1 1 50% ChREBP - / - 1 β 45 ACC1 ACC2 ChREBP1 - / - ACC ChREBP - / - A ACC1 ACC2 ChREBP β A 2. 2 46 FAS 7 A A FAS mrna ACC1 FAS SCD1 47 - / - FAS + /- diacylglycerol 48 FAS FASKO acyltransferase DGAT A 1 49 long chain acyl-coa synthetases1 ACSL1 2. 2. 1 ACC1 FAS ACC ACC1 ACC1 ACC2 ACC1 ACC2 5-tetradecyloxyl- FAS A β ACC1 ACC2 FASKOL PPAR α 265 kd β A FASKOL

128 32 FAS 60 DGAT1 - / - db /db β 50 FAS 61 DGAT2 - / - A β DGAT2 - / - 10% db /db DGAT2 2. 2. 2 SCD1 62 DGAT2 + /- SCD1 DGAT2 50% ob /ob SCD1 51 DGAT2 ob /ob SCD1 DGAT1 63 52 53 ob /ob SCD1 mrna DGAT1 VLDL leptin SCD1 64 mrna SCD1 ob /ob DGAT2 3. 1 54 55 SCD1 ab J /ab J ob /ob ab J / ab J ob /ob VLDL SCD1 ob /ob 2. 2. 4 A ACSL1 ACSL1 SCD1 ACSL 65 ACSL1 ob /ob ob / A ob 56 SCD1 β ob /ob 65 3T3 ACSL1 mrna / 56 ACSL1 ap2-nsrebp-1c 66 PPARα leptin ACSL1 mrna leptin SCD1 mrna ACSL1 β 67 Chiu ap2-nsrebp-1c ab J / ab J 68 ACSL1 ab J / ab J ap2-nsrebp-1c β SCD1 ap2-nsrebp-1c ACSL1 β SCD1 - / - β 57 SCD1 - / - β 69 ACSL1 AMPK ACC Ser-79 β ACC A 70 ACSL1 β 58 2. 2. 3 3- DGAT DGAT 3 β 59 DGAT DGAT1 DGAT2 β 59 DGAT1 DGAT2 3 1 60 DGAT1 A A 2 ACAT A 1 carnitine VLDL 60 DGAT2 palmitoyltransferase1 CPT1 monoacyglycerol acyltransferases MGAT β 3 SCD1 2 carnitine

2 129 palmitoyltransferase 2 CPT2 6 ~ 36 h A 71 A 76 MTP + /- β 76 CPT1 72 4 VLDL CPT1 2 CPT1A CPT1B CPT1A CPT1B VLDL 30 ~ 80 nm 77 VLDL CPT1 A apob100 78 MTTP ACC2 microsomal triglyceride transfer protein 79 A CPT1 CPT1 80 MTTP 73 Abu-Elheiga 74 ACC2 - / - VLDL MTTP - / - 9. 5 d A CPT1A 10. 5 d ACC2 - / - VLDL MTTP + /- β 14 C- A apob100 ACC2 ACC1 26% 81 O MTTP + /- ACC2 - / - MTTP + /- 82 VLDL A CPT1A MTTP + /- A 80% L-MTTP - / - Harada 44 ACC1 MTTP A L-MTTP - / - Wu 50 VLDL FAS 79 L-MTTP - / - VLDL A β A 40% 50% 79 A 5 A CPT1A A A 4 β 75 1 A A 4 A very long chain acyl-coa dehydrogenase VLCAD A long chain acyl-coa dehydrogenase LCAD A β VLDL medium chain acyl-coa dehydrogenase MCAD Asedium chain acyl-coa dehydrogenase SCAD 3 1 3 mitochondrial trifunctional protein MTP 76 β VLDL β MTP β MTP - / -

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